Angiotensin converting enzyme (ACE) is a carboxyl peptidase that converts the inactive precursor angiotensin I into angiotensin II. ACE is a key component of the renin-angiotensin system (RAS) and plays a very important role in the physiologic control of blood pressure and fluid balance. The physiologic actions of the RSA are more complex than simple blood pressure control, as evidenced by the phenotype of knockout mice that lack a functional renin-angiotensin system. During the first four years of this grant, this group has created and studied mice that lack ACE. These animals have very low systolic blood pressures, a variety of renal abnormalities, anemia, and reproductive abnormalities. This competitive application is to continue the study of these animals towards the goal of understanding the mechanisms by which the RAS influences normal and abnormal physiology. Specifically, the proposed experiments are designed to study 1) the role of the RAS in the fluid and hematological abnormalities present in ACE knockout mice, 2) the role of the RAS in the renal concentrating mechanism, and 3) the role of the local, tissue specific expression of ACE in regulating cardiovascular function.